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It is true that despite promising early studies, clinical application of microvolt T-wave alternans (MTWA) has become less clear, with both the MASTER (Microvolt T Wave Alternans Testing for Risk Stratification of Post-Myocardial Infarction Patients) trial (1) and the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) substudy (2) failing to demonstrate an association of MTWA with their primary end points. The issue is further muddied by the conflicting results from the ALPHA (T-wave alternans in patients with heart failure) study (3), in which MTWA predicted arrhythmic mortality in nonischemic cardiomyopathy patients. Although the explanation(s) for such divergent findings remain speculative, one possibility is that implantable cardioverter-defibrillator (ICD) shocks, which were used as end points in both the MASTER and SCD-HeFT trials, might be a poor surrogate for arrhythmic mortality due to lack of specificity. In a recent MTWA meta-analysis, Hohnloser et al. (4) concluded that MTWA studies in which ICD penetration was low and that used mortality as the primary end point generally show MTWA to be a powerful predictor of events. The reverse is true for studies such as MASTER and SCD-HeFT, in which ICD penetration was high and which used ICD shock end points.

Where to go from here with respect to MTWA is a matter of differing opinion, but for many, enthusiasm has been replaced by caution. Attempting to improve prediction through refining interpretation of the test (e.g., using MTWA magnitude as a continuous rather than dichotomous index of risk, possibly with adjustment for T-wave amplitude) has conceptual appeal but still requires clinical validation. In the MASTER trial, exploring different heart rate cut-off thresholds for defining positive and negative MTWA test results (i.e., onset heart rate and maximum negative heart rate) did not improve predictive value (5). Retrospective analysis of alternans amplitude as a risk index, as suggested by Dr. Madias, is certainly possible. In principle, additional refinements could also be made. For example, because MTWA is heart rate-dependent, overlap of patient daily heart rate with the onset heart rate for alternans could be a better index of risk than whether alternans is present at an arbitrary heart rate threshold of 110 beats/min. Whether trigger-substrate type relationships exist between MTWA and, for example, ventricular ectopy are largely unknown. Utility of MTWA as a component within a “suite” of noninvasive predictors is also under evaluation in other ongoing studies.

With respect to the concept of serial MTWA testing raised by Dr. Madias, all MASTER patients were in fact required to undergo annual MTWA testing. We previously reported that annual concordance between MTWA test results was relatively low, and by the end of the study, approximately two-thirds of patients had tested differently at least once (6). This finding supports study designs that include periodic MTWA testing during follow-up.

At a more conceptual level, it is important to recognize the difference between “routine” testing for MTWA and whether MTWA as a biological phenomenon participates in arrhythmia genesis or susceptibility. The optimist might say that we need to improve our understanding of how and when to test for MTWA through future research rather than reject the entire concept altogether.

(2008) Role of microvolt T-wave alternans in assessment of arrhythmia vulnerability among patients with heart failure and systolic dysfunction: primary results from the T-Wave Alternans Sudden Cardiac Death in Heart Failure Trial substudy. Circulation118:2022–2028.

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